Noninvasive Imaging in the Assessment of the Cardiopulmonary Vascular Unit
Noninvasive imaging plays a key role in both the diagnosis and management of patients with pulmonary hypertension (PH). In recent years, there have been 2 major changes in perspective of imaging in PH. The first was the realization that imaging should focus on the evaluation of not only the pulmonary pressures but also the cardiopulmonary unit (Figure 1).1,2 The second was the emergence of multimodality imaging with a complementary role for echocardiography, magnetic resonance (MRI), computed tomography, and positron emission tomography (PET).2–7 These techniques not only help in the diagnosis of PH but also help identify factors that determine risk and prognosis and gauge therapeutic effects on right ventricular (RV) function in patients with pulmonary arterial hypertension (PAH). Although echocardiography is the mainstay in the assessment of hemodynamic and ventricular function in PH, MRI has emerged as the gold standard for quantifying volumes, function, and flow in the right side of the heart.2–7 PET is also offering novel insights into perfusion and blood flow, metabolism, neurohormonal activation, and other molecular processes in the right side of the heart but is used mainly for research at this time. Catheterization of the right side of the heart remains the gold standard for defining PH and assessing hemodynamics both at rest and with exercise. Invasive assessment of cardiac output (CO) may, however, have limited accuracy when assumed instead of measured oxygen consumption is used to derive CO (eg, using the Fick method) or when thermodilution is used in the setting of a low-CO state.8–10
This review covers RV imaging studies performed in the field of PH and discusses recent advances in echocardiography and cardiac MRI and PET imaging for detailed assessment of RV function. The review starts with a discussion of important physiological considerations and unmet needs in imaging research of the right side of the heart in PH. Computed tomography angiography, which plays an important role in evaluating chronic thromboembolic PH, is not discussed extensively in this review.
Physiological Considerations
Although PH is a syndrome affecting the pulmonary vasculature, survival of patients with PH is closely related to RV function.1,11–14 The RV initially adapts to the increased afterload by increasing its wall thickness and contractility. These mechanisms are, however, often insufficient, and RV dysfunction eventually occurs. After the recent Fifth World Symposium on Pulmonary Hypertension, a definition of failure of the right side of the heart secondary to PH was adopted: “Right heart failure in the setting of PH can be defined as a complex clinical syndrome due to a suboptimal delivery of blood or elevated systemic venous pressure at rest or exercise as a consequence of elevated RV afterload.”2 The proposed definition takes into account both the systolic and diastolic characteristics of function of the right side of the heart, as well as physiological demands such as exercise.
In understanding RV adaptation to PH, one important metric that takes into account both contractility and afterload is ventriculo-arterial coupling. When in PH the increased pulmonary vascular afterload is matched by an adaptive increase in RV contractility, the RV is said to be coupled to the pulmonary arterial circulation.15 Altered ventriculo-arterial coupling occurs with increasing afterload, with some patients showing a better compensation or adaptability than others. Most of the metrics of RV function used in clinical practice today are a reflection of ventriculo-arterial coupling rather than contractility (load-independent measure).16 In fact, although contractility is increased in patients with PH, RV ejection fraction (RVEF), RV strain, or tricuspid plane annular excursion is often decreased.15,16 In addition, a recent study has also highlighted the importance of serial assessment of function of the right side of the heart in PAH, with patients with stable ventricular function showing good long-term outcomes.12 In comparisons of RV and left ventricular (LV) adaptation to pressure overload, one important distinction is the fact that the right side of the heart dilates early and that eccentric hypertrophy is, by far, the most common RV geometry. In the left side of the heart, both concentric hypertrophy and eccentric hypertrophy occur in response to systemic hypertension, and myocardial fibrosis is more common.17 Finally, although the focus is often placed on the RV, ongoing studies will determine whether right atrial function adds independent prognostic information in PH or failure of the right side of the heart.
Unmet Needs in Noninvasive Imaging of the Cardiopulmonary Unit in PH
Although imaging of the cardiopulmonary unit is a routine part of clinical evaluation, several unmet needs in the field remain (summarized in Table 1), which span from defining normal scaled reference values, to refining the definition of exercise-induced PH (EIPH), to developing integrative diagnostic and prognostic scores, to determining the best surrogate end point for research, and to developing novel physiological management strategies in PH. We anticipate that several of these questions will be answered within the next 5 to 10 years.
Field | Unmet Research Need in Imaging |
---|---|
Reference values | To establish normal scaled values for chambers of the right side of the heart in echocardiography (adjusted for age, sex, level of activity) |
Physiological indexes | To establish the best index of contractility, to determine physiological bases of deformation indexes, to determine and standardize methods to assess myocardial deformation, to develop better indexes to assess the septal contribution of the function of the right side of the heart, and to better determine the role of atrial function in patients with right heart disease. |
Screening | To develop novel imaging scores for screening patients at risk of PH that may incorporate strain imaging parameters, to develop and validate scores to identify patients with increased PVR in disease of the left side of the heart, and to standardize exercise or stress testing for screening of PH screening purposes |
Pathophysiology | To determine the best imaging correlate(s) for fibrosis of the right side of the heart and to refine molecular imaging of the right heart. This would be useful to predict recovery and arrhythmia potential in disease of the right side of the heart. Multimodality imaging will help in the search of genetic and epigenic factors modulating RV adaptation in PH by identifying better-defined phenotypes. |
Prognosis | To validate simple and reproducible imaging-based prediction scores in PAH. This will provide a better perspective of the complementary value of novel circulating biomarkers and will be useful for randomization or propensity matching. |
Physiological based therapeutic management | To determine how a physiology-based approach that incorporates metabolism, fibrosis, and ventriculo-arterial coupling can help tailor the management of acute and chronic failure of the right side of the heart. Specifically for surgical planning for end-stage PAH, determine whether strain imaging or markers of fibrosis can help identify which patients would benefit from heart-lung or double-lung transplantation.Three-dimensional imaging, including a 3-dimensional print model, may also guide patient-tailored interventional therapy. |
Surrogate end points | To determine whether function of the right side of the heart would be a better surrogate end point for phase 2 clinical trials than hemodynamic measures |
PAH indicates pulmonary arterial hypertension; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; and RV, right ventricular.
Echocardiography
Overview of Echocardiographic Evaluation
Transthoracic echocardiography is the mainstay in the assessment patients with PH.18,19 Basic assessment of the cardiopulmonary unit by echocardiography involves assessment of cardiac chamber size; metrics of RV function such as tricuspid annular plane systolic excursion, fractional area change, and myocardial performance indexes; valvular regurgitation or function; pulmonary hemodynamics; and septal curvature, which can integrate metrics on ventricular interdependence.16,20,21 Table 2 summarizes normative values for the measures of function of the right side of the heart, and Figure 2 illustrates some of these measures.16,22–31 As discussed in the following paragraphs, myocardial deformation imaging is also emerging as a useful modality for imaging the right side of the heart.
Metric | References | Comments |
---|---|---|
Systolic phase indexes | ||
RVEF | >50% | < 35% often considered as moderate RV systolic dysfunction |
RVFAC | >35% | Less than 25% denotes moderate RV systolic dysfunction |
TAPSE | >18 mm | Abnormal value suggested in ASE guideline <16 mm |
RVMPI–pulsed tissue | <0.55 | Nongeometric index of global systolic and diastolic function. Pseudonormalized values have been reported in patients with severe RV dysfunction |
Deformation indexes | ||
Global long. strain | <−25% | Severe often if >−15% by speckle tracking. RV values need to be better defined for clinical practice; average normal value around −2/s (longitudinal) |
Peak systolic SR | … | Ill defined |
Peak diastolic SR | Ill defined | |
Velocity metrics | ||
IVA | … | Depends on methodology; usually >2 m/s2 (considered less load dependent) |
S velocity | >12 cm/s | |
Diastolic metrics | ||
IVRT (TDI) corrected | <65 ms | IVRT divided by square root of RR interval |
HV systolic VTI | >55% | sHVF VTI/(sHVF VTI+dHVF VTI)<55% predicts RAP>8 mm Hg |
Pulmonary flow | ||
Pulmonary AT | > 93 ms | Has been shown useful to screen for PH |
Adapted from several references.22,24–30 ASE indicates American Society of Echocardiography; AT, acceleration time; d, diastolic; HV, hepatic vein; HVF, hepatic vein flow; IVA, myocardial acceleration during isovolumic contraction; IVRT, isovolumic relaxation time; long, longitudinal; PH, pulmonary hypertension; RAP, right atrial pressure; RV, right ventricular; RVEF, right ventricular ejection fraction; RVFAC, right ventricular fractional area change; RVMPI, right ventricular myocardial performance index; s systolic; S velocity, tissue Doppler systolic velocity; SR, strain rate; TAPSE, tricuspid annular systolic excursion; TDI, tissue Doppler imaging; and VTI velocity-time integral.
Several pearls are important in evaluating the cardiopulmonary unit by echocardiography. The most important pearl in evaluating patients with PH is that the focus of the study should not be limited to evaluation of RV systolic pressures (RVSPs) but rather should include evaluation of both systolic and diastolic parameters of the right side of the heart.22 This is especially important because prognosis in PH is strongly related to function of the right side of the heart; moreover, pulmonary pressures may decrease when function of the right side of the heart deteriorates and can thus be deceiving in the estimation of severity.2 A second pearl is that not all cases of increased right-sided systolic pressures are caused by PH; for example, pulmonary stenosis or a double-chambered RV can cause elevation of RVSP in the absence of PH. A third and associated pearl is that the cause of an increased RVSP does not necessarily lie within the pulmonary circulation per se. Rather, in many patients, the increase in RVSP relates to increased pulmonary venous pressure. Findings such as LV hypertrophy and increased left atrial size represent common and practical clues that strongly sway the diagnosis of PH toward pulmonary venous hypertension. A forth pearl in the assessment of PH is that, in the presence of severe hypertrophy or severe PA enlargement, a congenital cause of PH should be excluded and strong consideration for MRI should be given. Finally, in the presence of hypoxemia, evaluation of a right-to-left shunt through a patent foramen ovale should always be considered in the differential.
The following sections highlight recent controversies with regard to the noninvasive evaluation of pulmonary hemodynamics, the renewed interest in the use of exercise stress testing in the evaluation of PH, the use of scores to differentiate patients with PH and increased pulmonary vascular resistance (PVR) from patients with normal PVR, and the growing interest in the field of myocardial deformation imaging.
Controversies in Screening Patients for PH
There has been controversy recently about whether echocardiography is a useful screening method or is accurate for the evaluation of PH.20,32–37 Although earlier studies demonstrated an excellent correlation between echocardiographic estimates and pulmonary pressures measured invasively, the strength of this correlation has been challenged in recent studies.20,32,33,35–37 For example, in the landmark clinical study by Yock and Popp,37 there was an excellent association between Doppler and catheterization-derived RVSP of the right side of the heart, with a correlation coefficient of 0.93 and a standard error of the estimate of 8 mm Hg. In more recent studies by Fisher et al,34 the strength of this correlation has been challenged. These investigators found lower correlation coefficients, and in >52% of the patients, there was a >10-mm Hg estimated difference between the 2 techniques (n=63). The key question in interpreting these studies, however, is whether the quality of the signals (eg, Doppler envelope) was always appropriate for analysis. In addition, screening for PH does not necessarily require accurate prediction of pulmonary pressures; one index could be adequate for screening but not allow accurate prediction of pulmonary pressures. This brings us to another important pearl for the evaluation of PH, which is the fact that adequate screening should take into account multiple parameters, for example, estimates of pressures, pulmonary acceleration time, the presence or absence of a pulmonary notch, or septal curvature (systolic D shape of the LV), or supporting evidence of PH such as RV enlargement, an increase in isovolumic relaxation time, and, if further validated, a decrease in strain or strain-rate index (Table 3).21,38–41 Moreover, in future studies, screening algorithms should be tested in patients with very mild pulmonary vascular disease to identify the most reliable early markers of pulmonary vascular disease and dysfunction of the right side of the heart.
Parameters | Indexes |
---|---|
Assessment of pulmonary pressures by Doppler echocardiography (gradients) | RVSP=4×TRV2+RAPMPAP=4×peak PRV2DPAP=4×PRVED2+RAPMPAP=2 mm Hg+0.59 RVSP |
Estimation using pulmonary flow | MPAP=79−0.45(AT) |
Septal curvature | Systolic septal flattening reflects anatomic, hemodynamic, electric ventricular interdependence |
Supporting evidence | RV enlargement, ↑ RV IVRT, ↑ RAP |
Exercise-induced PH | Emerging field but signal acquisition may be difficult |
Investigational | Ongoing studies on RV strain and strain-rate imaging |
AT indicates acceleration time; DPAP, diastolic pulmonary artery pressure; IVRT, isovolumic relaxation time; MPAP, mean pulmonary artery pressure; PH, pulmonary hypertension; PRV, pulmonary regurgitation velocity; PRVED, pulmonary regurgitation end-diastolic velocity; RAP, right atrial pressure; RV, right ventricular. RVSP, right ventricular systolic pressure; and TRV, tricuspid regurgitation velocity. Adapted from several references.18,19,28,42,43
Differentiating Patients With Increased PVR
Another important interest in the evaluation of PH has been differentiating patients with normal from those with increased PVR. Two different approaches have been described in the literature. The first uses multiple approximation formulas that estimate pulmonary capillary wedge pressure and CO, and the other uses a score that focuses on key differentiating features.18,19 The first approach has the advantage of being simpler but is limited by the cumulative effects of several measuring errors. The second approach has the advantage of taking into account remodeling, hemodynamics, and epidemiological features but does not lead to quantification of PVR. In a recent study, Opotowsky et al44 developed a simple score based on left atrial size, the ratio of E to e′, and acceleration time or the presence of a pulmonary notch to discriminate patients with increased PVR. Of note, patients with left-sided heart failure without increased PVR are often much older with more comorbidities, as was shown by Thenappan et al.45 Validation of these scores by several research groups is currently underway.
EIPH and Dynamic Testing in PH
In recent years, there have been several key studies on exercise testing in patients with PH. The renewed interest in exercise in PH is based on the premise that, although patients may have normal pulmonary pressures at rest, any increase in these pressures with exercise would be significantly higher than in healthy control subjects. Previously, EIPH was defined as a mean pulmonary arterial pressure (mPAP) >30 mm Hg with exercise; however, this definition was abandoned because it does not take into account changes in CO. On the basis of both invasive and noninvasive data, several investigators have now shown that the mPAP-CO relationship can be approximated by a linear relationship.46–49 This is unlike the systemic circulation in which several slopes are needed to describe the systemic pressure–CO relationship. In control subjects, the slope of the mPAP-CO relationship is usually <1.5 to 2.5 mm Hg·min·L−1, with older healthy individuals having higher average slope values.43,50,51 Although no consensus has yet been reached on the definition of EIPH, an mPAP-CO slope >3 mm Hg·min·L−1 or an mPAP >30 mm Hg at a CO of 10 L/min (approximation because the slope does not perfectly intersect the zero origin) could be considered a potential criterion. Patients with higher-than-normal mPAP deserve a clinical evaluation to exclude the 2 major causes of EIPH: conditions of the left side of the heart (eg, dynamic mitral insufficiency) or increased PVR (eg, PAH or late closure of an atrial septal defect).
There are several noteworthy studies in the literature; here, we chose to highlight three recent studies. Grünig et al46 showed in a large multicenter study that relatives of patients with PAH had a significantly higher pulmonary hypertensive response with exercise compared with control subjects and that this was higher in patients with BMPR2 mutations. In their study, PH was defined by a tricuspid regurgitation velocity jet >3.08 cm/s based on a 90% value of control subjects. This study was followed by the study by D’Alto et al,52 which showed that patients with New York Heart Association class I or II scleroderma without evidence of PH at rest had a greater incidence of EIPH, defined as the upper limits of control subjects (13%). Furthermore, they demonstrated that the slope of change in the relationship between PASP and cardiac index was significantly greater than normal. In the field of degenerative mitral regurgitation, Magne et al53 also recently showed that EIPH, defined as an RVSP >60 mm Hg with exercise, better discriminates patients who progress to symptomatic disease compared with rest RVSP. Although these results are very promising, some challenges remain as we move forward such as proving the feasibility and reproducibility of these tests in clinical practice and standardizing the pulmonary pressure–CO or pulmonary pressure–cardiac index slope criteria. In addition, demonstrating a potential value when added to a multiparameter screening approach would be an important step at this time.
Further insight into RV function during (endurance) exercise was provided by a recent study by La Gerche et al.54 Whether it was due to EIPH or prolonged volume loading, the authors showed that, immediately after an endurance race, RV volumes increase and functional measures (ie, tricuspid plane annular excursion and RVEF) decrease, whereas LV volumes decrease and LV function remains unaltered. Reflective of a degree of cardiac injury during endurance exercise, B-type natriuretic peptide and troponin levels increased after a race and correlated with reductions in RVEF. Although RV function mostly recovered by 1 week after the race, evidence of localized fibrosis was demonstrated in the interventricular septum of 5 of 39 athletes who had greater cumulative exercise exposure and lower RVEF than those with normal cardiovascular magnetic resonance. The long-term clinical significance of these findings requires further study but may include the generation of arrhythmias.
Myocardial Deformation Imaging of the RV: Holy Grail or Flavor du Jour
In a recent editorial, Reichek55 noted that there have been several hundred publications on RV myocardial imaging over the past few years. Considering this impressive body of literature, an obvious question is, How does myocardial deformation imaging affect screening or prediction of outcome in patients with PH? As shown in Figure 3A, there are 4 essential components of myocardial imaging: velocities, displacement, strain (normalized deformation), and strain rate.42,57 Either spatial or temporal integration or derivation links the different concepts together. Methodologically, imaging can be accomplished with either tissue Doppler imaging or speckle tracking. Tissue Doppler imaging appears to be ideal for determining velocity profiles (Figure 3B), whereas speckle tracking imaging may be superior for strain and strain-rate imaging. In addition, global strain of the ventricle can be assessed by manually measuring 2-dimensional changes in entire wall segments. The measures that have captured more attention include global RV strain, peak systolic strain rate, and early diastolic strain rate (Figure 3C and 3D). Analysis of right strain or strain rate involves a comparison of peak values, timing of deformation, or comparative left values. Although very interesting conceptually, the technology used to derive these measures makes several assumptions; thus, quality control cannot be overemphasized in the interpretation of the results.58,59 Ongoing studies will determine the best methodology to use for strain measurements.
For screening purposes, Kittipovanonth et al40 have shown that, in patients with early PH (n=30), both RV peak strain and strain rate were significantly lower than in control subjects (n=40), whereas there were no significant differences in RV dimension, tricuspid plane annular excursion, RV fractional area change, or RV myocardial performance indexes. In an earlier study by Rajdev et al,41 RV free wall strain was significantly lower than in control subjects, whereas there were no difference in strain rate measures. Future studies are needed to determine the sequence of change in deformation imaging in patients with early pulmonary vascular disease.
Fine et al60 recently published the largest study investigating the value of strain imaging in PH (n=406 patients with PH) for outcome prediction. They demonstrated that peak longitudinal free wall strain was independently associated with outcome, along with log N-terminal brain natriuretic peptide levels and World Health Organization functional class. Several key messages emerge from their study. First, outcome prediction in PAH can probably be simplified by the use of quantitative indexes of RV function. Second, strain measurement could offer a simpler metric in the echocardiographic evaluation of the RV. One of the merits of their study is the inclusion of all the usual 2-dimensional and time indexes of RV function. An important implication of this study is that this could help improve randomization between studies and potentially help tailor therapy in intermediate-risk groups. Table 4 places the study of Fine et al in context with recent outcome studies in PAH.3–5,60–63
Study | Year | n* | Comment on the Study |
---|---|---|---|
Yeo et al63 | 1998 | 53 | First study to demonstrate the prognostic value of RVMPI |
Raymond et al4 | 2002 | 81 | First study to suggest the potential incremental value of right atrial size in PAH |
Forfia et al3 | 2006 | 47 | First study to suggest the incremental value of TAPSE in prognostic assessment of PAH |
Kane et al62 | 2011 | 484 | Places into perspective the incremental value of echocardiography compared with other scores |
Ernande et al61 | 2012 | 142 | Suggests the prognostic importance of isovolumic contraction velocities in patients with PAH and CTEPH |
Fine et al60 | 2013 | 300 | First study to demonstrate the independent predictive value of RV strain when taking into account the different functional indexes of the right side of the heart |
CTEPH indicates chronic thromboembolic pulmonary hypertension; PAH, pulmonary arterial hypertension; RV, right ventricular; RVMPI, right ventricular myocardial performance index; and TAPSE, tricuspid annular plane systolic excursion.
*
The number of patients in the different studies.
Physiologically, however, it is important to emphasize that strain or strain-rate measures are not load-independent metrics of function of the right side of the heart and that further experimental validation is needed. In the future, the study of strain-based contractility indexes may also help improve prediction. Several laboratories are currently investigating the added value of strain/afterload ratios.
Three-Dimensional Echocardiographic Imaging of the Right Side of the Heart
Reliable 3-dimensional RV echocardiographic imaging has also been an active area of research but has not yet reached routine clinical practice.64 To prove the incremental value of 3-dimensional imaging for predicting outcome in PH, a very large sample size will be required. Multiplane imagining of the RV may, however, be extremely helpful in securing proper 4-chamber view alignment.
In summary, echocardiography can provide structural and functional assessment of both the RV and the proximal pulmonary circulation and is therefore a useful and powerful tool in the assessment of the RV–pulmonary vascular unit, particularly when novel applications like strain imaging, 3-dimensional echocardiography, and simple scores are used.
Cardiac MRI
Volumetric Measurements
MRI has become the gold standard to noninvasively measure RV mass, volumes, and function in a reproducible, accurate manner.65–68 The volumetric measurements by cardiac MRI are particularly important for monitoring PAH patients on medical treatment. The presence of a decreased stroke volume, increased RV volumes, and a decreased LV end-diastolic volume measured at baseline is associated with a poor prognosis.69 A subsequent further increase in RV volumes and a decrease in stroke volume during treatment are clear signs of progressive RV failure and can be observed before failure becomes clinically manifest.7,12 This is illustrated in Figure 4, which shows a patient with progressive RV dilatation over the years together with a decrease in stroke volume, preceding clinical failure. Close monitoring of RV volumes and function offers the possibility for early therapeutic interventions, but the impact of such a strategy on patient outcomes has yet to be studied. Sex differences and age need to be considered during the interpretation of RV volumes and function,70,71 and appropriate corrections for these factors may become important in future studies.72
RV Mass
According to the Laplace law (ie, wall stress equals intraluminal pressure times chamber internal radius divided by wall thickness), RV hypertrophy in response to pressure-overloaded conditions is a way to reduce RV wall stress and thus should be considered as part of the adaptive remodeling process.73 The RV free wall, the trabeculae, and the papillary muscles are all involved in the hypertrophic process.74 The prognostic value of changes in RV mass in PAH is small and seems limited to patients with scleroderma PAH.69,75,76 The limited clinical value of the assessment of RV mass compared with RV volumes is perhaps explained by the fact that RV hypertrophy both reflects the severity of pulmonary vascular remodeling (negative impact) and is part of the normal adaptive process to an increased load (positive response).77 For example, despite a similar elevation in PAP, patients with Eisenmenger syndrome have a greater amount of RV hypertrophy compared with patients with idiopathic PAH, which is associated with better RV function and survival.78,79 For this reason, the assessment of RV mass as a single parameter is not informative. Recent advances in MRI, however, allow a more in-depth study of the RV myocardium, including contractile properties, perfusion, and even molecular imaging.
RV Function and Myocardium
Global RV systolic function is preferably measured by RVEF. RVEF is accurately measured by MRI and provides important prognostic information in treatment-naïve patients and during follow-up.12,69 However, this measurement is not a parameter of intrinsic RV contractility but is affected by preload, afterload, contractility, ventricular synchrony, valvular regurgitation, and shunt fraction, all at the same time.11,80
A method to assess the shortening of the RV myocardium in the transversal and longitudinal planes has been described by Kind et al.81 Changes in transversal plane movements are sensitive enough to detect early signs of progressive RV failure,82 but this parameter is determined by movements of the RV free wall and the septum and is highly load dependent. MRI tagging techniques are considered the reference techniques to measure the relative amount of myocardial wall deformation (segmental strain), the velocity of deformation (strain rate), and synchrony (ie, timing of mechanical activation and relaxation between wall segments). All these parameters can be determined in circumferential, longitudinal, and radial axes. In healthy subjects, there is a predominantly longitudinal rather than circumferential wall deformation, resulting in a bellows-like or peristaltic action of the RV. Normal wall deformation is generally larger at the basal and apical segments than at the midsegment.83 Patients with PH show an altered pattern with a globally reduced longitudinal and circumferential wall deformation.84 Furthermore, it has been found that regional longitudinal wall deformation can already be disturbed at the time that global RV function is still intact, implying that changes in regional measures could be sensitive parameters to detect early RV dysfunction in PAH.85
Insight into the global structure of the RV myocardium by MRI can be obtained by delayed contrast enhancement imaging with gadolinium or by T1 image mapping. With the use of gadolinium contrast, it was found that delayed contrast enhancement appeared at the interventricular insertion points and might be a reflection of focal fibrosis.86–89 The extent of delayed contrast enhancement was strongly correlated with increased RV mass, volumes, and pulmonary pressures (ie, RV wall stress).88,90 However, despite being very sensitive to small areas of regional fibrosis, delayed contrast enhancement techniques are not able to depict more diffuse fibrosis because the technique depends on the comparison with normal reference areas of myocardium. T1 mapping may overcome this problem by directly quantifying T1 values for each voxel in the myocardium, enabling the visualization of diffuse disease. It has been shown that T1 mapping of the RV myocardium is feasible even in healthy humans. The normal T1 time of the RV is significantly longer compared with the LV, which is most likely explained by the naturally higher collagen content of the RV.91 No studies have been published so far to study the impact of pressure overload on T1 time of the RV.
Ventricular Interdependency
A feature of the failing RV is the prolongation of the systolic contraction time compared with the LV contraction time, leading to a leftward shift of the septum at the end of RV contraction, during which time the LV is already in its relaxing phase.92 Of interest, in these cases, the RV will contract after closure of the pulmonary valve, resulting in a so-called postsystolic contraction period.93 Ventricular interdependency should be clearly interpreted as a sign of RV failure and can be measured by MRI by assessing the RV septum configuration94 and differences in contraction time92 or by the impact of ventricular interdependency on LV volumes.95
Assessing Myocardial Perfusion by Cardiac MRI
Myocardial perfusion reserve can be assessed by cardiac MRI after peripheral intravenous injection of an agent such as adenosine. In a study of 25 patients referred for PAH evaluation, myocardial perfusion reserve indexes (for both the RV and LV) in the PAH group were significantly lower than those in control individuals. Furthermore, RV and LV myocardial perfusion reserve indexes were inversely associated with mPAP and RV stroke work index, as well as with other measures of RV workload, systolic function, and remodeling, suggesting that reduced myocardial perfusion may contribute to poor RV performance in patients with PAH.96 Decreased coronary perfusion has also been demonstrated in PAH.97 The significance and usefulness of these findings in the assessment of RV function in PH remain to be determined in larger cohorts.
Molecular and Perfusion Imaging
Magnetic Resonance Spectroscopy
Magnetic resonance spectroscopy is an older technique that provides indirect information on cardiac metabolism without the need to administer a tracer. There is limited experience98 with the technique in PAH, however. 31Phophorus magnetic resonance spectroscopy studies performed in patients with advanced LV failure have repeatedly demonstrated decreased myocardial levels of creatine and ATP and correlations between these levels and survival.99
RV Metabolic Remodeling
Different pathological states of the LV myocardium are characterized by a decreased uptake of fatty acids.100,101 A decreased uptake of fatty acids was also shown to occur in the pressure-overloaded human RV through the use of single-photon emission computed tomography, a finding that was associated with impaired RV function and a poor prognosis.102 Fatty acid uptake can also be estimated by the use of PET with 11C-palmitate tracers101,103; however, such studies have not yet been performed in PAH. When fatty acid uptake is reduced, glucose becomes the alternative source of energy. In RV failure (at least experimentally), ATPs are increasingly generated through glycolysis rather than through glucose oxidation.104 RV myocardial glucose uptake can be quantified by PET with the use of 18F-2-deoxy-2-fluoro-d-glucose (18F-FDG) tracers,105 and some studies have demonstrated an increase in the ratio of RV to LV glucose uptake in PAH. However, it remains unclear whether this increased ratio is explained by an increased RV glucose uptake106–108 or a decreased LV uptake.109 Inconsistent results have been reported when it comes to the correlation between quantitative changes in glucose metabolism and changes in RV load and function.105,108–112 The differences between study results are perhaps due to differences in patient populations, scanning protocols, and data analysis. Preclinical studies have suggested that the metabolic shift toward glycolysis may not be sustained during the progression of RV failure,113 which not only complicates the comparison of different study populations but also brings into question the usefulness of RV 18F-FDG uptake as a biomarker in PAH. Importantly, it currently remains unclear whether changes in metabolism in the RV of PAH patients can be regarded as adaptive or as indicative of pathological remodeling.
RV Oxygen Consumption and Blood Flow
With a combination of 15O-labeled tracers (15O-H2O, 15O-CO, and 15O-O2) or, more practically, with 11C-acetate tracers, PET imaging allows the estimation of RV myocardial oxygen consumption (MVo2).114,115 Resting MVo2 is significantly elevated in patients with PAH,112,116 whereas New York Heart Association class III patients show a higher MVo2 than New York Heart Association class II patients (see Figure 5). The fact that RV power output is similar in class II and III PAH patients shows that, during the course of PAH, RV efficiency is progressively reduced.112
RV Angiogenesis
Whether related to a decreased overall coronary perfusion, failure of the right side of the heart in animal models of PH is clearly associated with impairment in angiogenesis relative to the degree of hypertrophy.113,117 Major angiogenic pathways converge on signaling via vascular endothelial growth factor and integrins, and novel PET imaging strategies were developed to directly measure angiogenesis with 64CU-labeled vascular endothelial growth factor118 and 18F arginine-glycine-aspartic acid peptide (with affinity for the αvβ3 integrin) tracers. Imaging of angiogenesis after myocardial infarction was feasible in rats119–121 and was applied in a patient 2 weeks after myocardial infarction.122 These techniques have yet to be used in patients with PAH.
RV Neurohormonal System
Preclinical studies have provided evidence for a role of dysfunctional neurohormonal signaling in the development of RV failure in PAH.118 Several PET tracers are available to study components of the sympathetic nervous system. Presynaptic (re)uptake of norepinephrine, assessed with the use of the norepinephrine analog 11C- meta-hydroxyephedrine (HED), was shown to be impaired in patients with LV cardiomyopathies, and the impairment was associated with poor outcome. Figure 6 shows an example of 11C-HED retention in a patient with PAH before and after β-blocker treatment. Likewise, a reduced density of β-adrenoceptors, as reflected by a decreased uptake of the tracers 11C-CGP-12177 and11C-CGP-12388, was associated with worse survival of patients with LV failure.123–125 The increased renin-angiotensin-aldosterone system activity in PAH reflects disease severity.126 PET imaging with11C-KR31173 tracers could allow the quantification of cardiac angiotensin receptor density127 and may provide important pathophysiological data in patients with PAH.
RV Apoptosis
Apoptosis has been attributed with a critical role in the development of heart failure.128 During the process of apoptosis, the phospholipid phosphatidylserine is expressed on the outer cell membrane and serves as a signal for cell removal by macrophages.129 Annexin is a protein that binds to phosphatidylserine, and single-photon emission computed tomography imaging showed increased 99Tc-labeled annexin V uptake in the failing LV130 and in rejected cardiac transplants.131 Similar results were obtained in PH animal models, but these data have not yet been confirmed in patients with PAH.132
Hybrid PET-MRI
Hybrid PET-MRI allows simultaneous molecular and anatomic imaging, and its application may improve the understanding of RV failure. A major limitation of hybrid systems with MRI is that information required for attenuation correction of nuclear images is not provided. Recently, the first hybrid PET-MRI results of patients with myocardial infarction have been published and have demonstrated high image quality.133–135
Summary and Conclusions
We predict that cardiac MRI and PET will significantly contribute to a better understanding of the pathophysiological processes that lead to the development of chronic RV failure in PAH. Imaging studies have demonstrated that, in the setting of chronic pressure overload, the RV compensates enduringly to sustain CO by an increase in wall mass, dilatation, and contractility and marked changes in the RV shape. With the passage of time, these compensatory mechanisms fail, resulting in increased wall stress and impaired global RV function. Other factors that might contribute to disturbed RV function are a reduced wall deformation and an inefficient RV contraction pattern. The resulting interventricular asynchrony is associated with leftward septum bowing, impaired LV filling, and decreased stroke volume. Furthermore, the RV becomes mechanically insufficient: More oxygen is required for a comparable power output. At the same time, RV oxygen delivery is impaired and tissue oxygenation is reduced. Alterations in myocardial metabolism have been observed in PAH, but their overall relevance and whether they represent cause or consequence of RV failure remain unclear.
With the current evidence, it can confidently be stated that RV imaging parameters measured at baseline correlate with exercise capacity and functional class and predict survival.69,136 Moreover, RV imaging parameters have been shown to respond to treatment,35,137 and changes in these parameters after treatment reflect altered exercise capacity138 and predict subsequent survival.12 What is lacking at this point, however, is the demonstration of reliable monitoring and improved overall clinical outcome when a treatment strategy based on specific imaging parameters is used.
In the near future, it can be expected that the importance of changes in cellular functions and signaling pathways will become clearer and the changes will be “imageable.” This might allow a regional and quantifiable analysis of processes such as angiogenesis, apoptosis, and neurohormonal factors. Table 5 provides an overview of currently available clinical imaging tracers that could be relevant for the assessment of molecular processes of RV diseases in patients. In addition, recent developments in (hybrid) PET and MRI might allow an integrated RV assessment in vivo. They will likely provide an important basis for simultaneous measurements of multiple myocardial disease processes.
Function | Tracer MRI | Tracer PET |
---|---|---|
Angiogenesis | 18F-arginine-glycine-aspartic acid peptide αvβ3 integrins121* | |
Apoptosis | Iron-labeled annexin V139*Synaptotagmin C2A140* | 18F-annexin V141* |
Metabolism | ATP, phosphocreatinine98*142† | 11C-palmitate103*18F-fluoro-2-deoxy-d-glucose112 |
Oxygen consumption | 11C-acetate11515O-H2O, 15O-CO, 15O-O2112,114 | |
Neuroreceptors:sympathetic signaling | 11C- hydroxyephedrine124,125*11C-CGP-12177125,143*11C-CGP-12388144* | |
Parasympathetic signaling | 11C-MQNB145* | |
Renin-angiotensin-aldosterone system | 11C-KR31173127* |
MRI indicates magnetic resonance imaging; and PET, positron emission tomography.
*
Previously performed in patients with left ventricular failure but not yet applied in patients with right ventricular failure.
†
Using 31phosphorus magnetic resonance spectroscopy
Acknowledgments
We thank Onno Spruijt, MD, Hans Harms, PhD, Joseph Wu, MD, PhD, Andre Denault, MD, PhD, Elie Fadel, MD, PhD, and Olaf Mercier, MD, PhD, for their support of this review.
References
1.
Champion HC, Michelakis ED, Hassoun PM. Comprehensive invasive and noninvasive approach to the right ventricle-pulmonary circulation unit: state of the art and clinical and research implications. Circulation. 2009;120:992–1007. doi: 10.1161/CIRCULATIONAHA.106.674028.
2.
Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF, Hassoun PM. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 2013;62(suppl):D22–D33. doi: 10.1016/j.jacc.2013.10.027.
3.
Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, Chamera E, Corretti MC, Champion HC, Abraham TP, Girgis RE, Hassoun PM. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med. 2006;174:1034–1041. doi: 10.1164/rccm.200604-547OC.
4.
Raymond RJ, Hinderliter AL, Willis PW, Ralph D, Caldwell EJ, Williams W, Ettinger NA, Hill NS, Summer WR, de Boisblanc B, Schwartz T, Koch G, Clayton LM, Jöbsis MM, Crow JW, Long W. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39:1214–1219.
5.
Forfia PR, Vachiéry JL. Echocardiography in pulmonary arterial hypertension. Am J Cardiol. 2012;110(suppl):16S–24S. doi: 10.1016/j.amjcard.2012.06.012.
6.
Vonk-Noordegraaf A, Souza R. Cardiac magnetic resonance imaging: what can it add to our knowledge of the right ventricle in pulmonary arterial hypertension? Am J Cardiol. 2012;110(suppl):25S–31S. doi: 10.1016/j.amjcard.2012.06.013.
7.
Peacock AJ, Vonk Noordegraaf A. Cardiac magnetic resonance imaging in pulmonary arterial hypertension. Eur Respir Rev. 2013;22:526–534. doi: 10.1183/09059180.00006313.
8.
Wolf A, Pollman MJ, Trindade PT, Fowler MB, Alderman EL. Use of assumed versus measured oxygen consumption for the determination of cardiac output using the Fick principle. Cathet Cardiovasc Diagn. 1998;43:372–380.
9.
Fakler U, Pauli C, Hennig M, Sebening W, Hess J. Assumed oxygen consumption frequently results in large errors in the determination of cardiac output. J Thorac Cardiovasc Surg. 2005;130:272–276. doi: 10.1016/j.jtcvs.2005.02.048.
10.
Mauritz GJ, Marcus JT, Boonstra A, Postmus PE, Westerhof N, Vonk-Noordegraaf A. Non-invasive stroke volume assessment in patients with pulmonary arterial hypertension: left-sided data mandatory. J Cardiovasc Magn Reson. 2008;10:51. doi: 10.1186/1532-429X-10-51.
11.
Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, Long CS, Rubin LJ, Smart FW, Suzuki YJ, Gladwin M, Denholm EM, Gail DB; National Heart, Lung, and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure. Circulation. 2006;114:1883–1891. doi: 10.1161/CIRCULATIONAHA.106.632208.
12.
van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra A, Marques KM, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol. 2011;58:2511–2519.
13.
Bristow MCR, Zisman LS, Lowes BD, Abraham WT, Badesch DB, Groves BM, Voelkel NF, Lynch DM, Quaife RA. The pressure-overloaded right ventricle in pulmonary hypertension. Chest. 1998;114(suppl):101S–106S.
14.
Morrison D, Goldman S, Wright AL, Henry R, Sorenson S, Caldwell J, Ritchie J. The effect of pulmonary hypertension on systolic function of the right ventricle. Chest. 1983;84:250–257.
15.
Kuehne T, Yilmaz S, Steendijk P, Moore P, Groenink M, Saaed M, Weber O, Higgins CB, Ewert P, Fleck E, Nagel E, Schulze-Neick I, Lange P. Magnetic resonance imaging analysis of right ventricular pressure-volume loops: in vivo validation and clinical application in patients with pulmonary hypertension. Circulation. 2004;110:2010–2016. doi: 10.1161/01.CIR.0000143138.02493.DD.
16.
Guihaire J, Haddad F, Boulate D, Decante B, Denault AY, Wu J, Hervé P, Humbert M, Dartevelle P, Verhoye JP, Mercier O, Fadel E. Non-invasive indices of right ventricular function are markers of ventricular-arterial coupling rather than ventricular contractility: insights from a porcine model of chronic pressure overload. Eur Heart J Cardiovasc Imaging. 2013;14:1140–1149. doi: 10.1093/ehjci/jet092.
17.
Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med. 1991;114:345–352.
18.
Milan A, Magnino C, Veglio F. Echocardiographic indexes for the non-invasive evaluation of pulmonary hemodynamics. J Am Soc Echocardiogr. 2010;23:225–239; quiz 332–334. doi: 10.1016/j.echo.2010.01.003.
19.
Lang IM, Plank C, Sadushi-Kolici R, Jakowitsch J, Klepetko W, Maurer G. Imaging in pulmonary hypertension. JACC Cardiovasc Imaging. 2010;3:1287–1295. doi: 10.1016/j.jcmg.2010.09.013.
20.
Haddad F, Zamanian R, Beraud AS, Schnittger I, Feinstein J, Peterson T, Yang P, Doyle R, Rosenthal D. A novel non-invasive method of estimating pulmonary vascular resistance in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr. 2009;22:523–529. doi: 10.1016/j.echo.2009.01.021.
21.
Haddad F, Guihaire J, Skhiri M, Denault AY, Mercier O, Al-Halabi S, Vrtovec B, Fadel E, Zamanian RT, Schnittger I. Septal curvature is marker of hemodynamic, anatomical, and electromechanical ventricular interdependence in patients with pulmonary arterial hypertension. Echocardiography. 2014;31:699–707. doi: 10.1111/echo.12468.
22.
Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. Right ventricular function in cardiovascular disease, part I: anatomy, physiology, aging, and functional assessment of the right ventricle. Circulation. 2008;117:1436–1448. doi: 10.1161/CIRCULATIONAHA.107.653576.
23.
Shiran H, Zamanian RT, McConnell MV, Liang DH, Dash R, Heidary S, Sudini NL, Wu JC, Haddad F, Yang PC. Relationship between echocardiographic and magnetic resonance derived measures of right ventricular size and function in patients with pulmonary hypertension. J Am Soc Echocardiogr. 2014;27:405–412. doi: 10.1016/j.echo.2013.12.011.
24.
Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller NB. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23:685–713; quiz 786. doi: 10.1016/j.echo.2010.05.010.
25.
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise J, Solomon S, Spencer KT, St. John Sutton M, Stewart W; American Society of Echocardiography’s Nomenclature and Standards Committee; Task Force on Chamber Quantification; American College of Cardiology Echocardiography Committee; American Heart Association; European Association of Echocardiography, European Society of Cardiology. Recommendations for chamber quantification. Eur J Echocardiogr. 2006;7:79–108. doi: 10.1016/j.euje.2005.12.014.
26.
Fine NM, Shah AA, Han IY, Yu Y, Hsiao JF, Koshino Y, Saleh HK, Miller FA, Oh JK, Pellikka PA, Villarraga HR. Left and right ventricular strain and strain rate measurement in normal adults using velocity vector imaging: an assessment of reference values and intersystem agreement. Int J Cardiovasc Imaging. 2013;29:571–580. doi: 10.1007/s10554-012-0120-7.
27.
Vogel M, Schmidt MR, Kristiansen SB, Cheung M, White PA, Sorensen K, Redington AN. Validation of myocardial acceleration during isovolumic contraction as a novel noninvasive index of right ventricular contractility: comparison with ventricular pressure-volume relations in an animal model. Circulation. 2002;105:1693–1699.
28.
Fahmy Elnoamany M, Abdelraouf Dawood A. Right ventricular myocardial isovolumic relaxation time as novel method for evaluation of pulmonary hypertension: correlation with endothelin-1 levels. J Am Soc Echocardiogr. 2007;20:462–469. doi: 10.1016/j.echo.2006.10.003.
29.
Lanzarini L, Fontana A, Campana C, Klersy C. Two simple echo-Doppler measurements can accurately identify pulmonary hypertension in the large majority of patients with chronic heart failure. J Heart Lung Transplant. 2005;24:745–754. doi: 10.1016/j.healun.2004.03.026.
30.
Nageh MF, Kopelen HA, Zoghbi WA, Quiñones MA, Nagueh SF. Estimation of mean right atrial pressure using tissue Doppler imaging. Am J Cardiol. 1999;84:1448–51, A8.
31.
Guihaire J, Bogaard HJ, Flécher E, Noly PE, Mercier O, Haddad F, Fadel E. Experimental models of right heart failure: a window for translational research in pulmonary hypertension. Semin Respir Crit Care Med. 2013;34:689–699. doi: 10.1055/s-0033-1355444.
32.
Fisher MR, Mathai SC, Champion HC, Girgis RE, Housten-Harris T, Hummers L, Krishnan JA, Wigley F, Hassoun PM. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum. 2006;54:3043–3050. doi: 10.1002/art.22069.
33.
Arcasoy SM, Christie JD, Ferrari VA, Sutton MS, Zisman DA, Blumenthal NP, Pochettino A, Kotloff RM. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med. 2003;167:735–740. doi: 10.1164/rccm.200210-1130OC.
34.
Fisher MR, Forfia PR, Chamera E, Housten-Harris T, Champion HC, Girgis RE, Corretti MC, Hassoun PM. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179:615–621. doi: 10.1164/rccm.200811-1691OC.
35.
Hinderliter AL, Willis PW, Barst RJ, Rich S, Rubin LJ, Badesch DB, Groves BM, McGoon MD, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Koch G, Li S, Clayton LM, Jöbsis MM, Blackburn SD, Crow JW, Long WA. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension: Primary Pulmonary Hypertension Study Group. Circulation. 1997;95:1479–1486.
36.
Lafitte S, Pillois X, Reant P, Picard F, Arsac F, Dijos M, Coste P, Dos Santos P, Roudaut R. Estimation of pulmonary pressures and diagnosis of pulmonary hypertension by Doppler echocardiography: a retrospective comparison of routine echocardiography and invasive hemodynamics. J Am Soc Echocardiogr. 2013;26:457–463. doi: 10.1016/j.echo.2013.02.002.
37.
Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation. 1984;70:657–662.
38.
Chemla D, Castelain V, Hervé P, Lecarpentier Y, Brimioulle S. Haemodynamic evaluation of pulmonary hypertension. Eur Respir J. 2002;20:1314–1331.
39.
Chemla D, Castelain V, Humbert M, Hébert JL, Simonneau G, Lecarpentier Y, Hervé P. New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure. Chest. 2004;126:1313–1317. doi: 10.1378/chest.126.4.1313.
40.
Kittipovanonth M, Bellavia D, Chandrasekaran K, Villarraga HR, Abraham TP, Pellikka PA. Doppler myocardial imaging for early detection of right ventricular dysfunction in patients with pulmonary hypertension. J Am Soc Echocardiogr. 2008;21:1035–1041. doi: 10.1016/j.echo.2008.07.002.
41.
Rajdev S, Nanda NC, Patel V, Singh A, Mehmood F, Vengala S, Fang L, Dasan V, Benza RL, Bourge RC. Tissue Doppler assessment of longitudinal right and left ventricular strain and strain rate in pulmonary artery hypertension. Echocardiography. 2006;23:872–879. doi: 10.1111/j.1540-8175.2006.00337.x.
42.
Jamal F, Bergerot C, Argaud L, Loufouat J, Ovize M. Longitudinal strain quantitates regional right ventricular contractile function. Am J Physiol Heart Circ Physiol. 2003;285:H2842–H2847. doi: 10.1152/ajpheart.00218.2003.
43.
Naeije R, Chesler N. Pulmonary circulation at exercise. Compr Physiol. 2012;2:711–741. doi: 10.1002/cphy.c100091.
44.
Opotowsky AR, Ojeda J, Rogers F, Prasanna V, Clair M, Moko L, Vaidya A, Afilalo J, Forfia PR. A simple echocardiographic prediction rule for hemodynamics in pulmonary hypertension. Circ Cardiovasc Imaging. 2012;5:765–775. doi: 10.1161/CIRCIMAGING.112.976654.
45.
Thenappan T, Shah SJ, Gomberg-Maitland M, Collander B, Vallakati A, Shroff P, Rich S. Clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction. Circ Heart Fail. 2011;4:257–265. doi: 10.1161/CIRCHEARTFAILURE.110.958801.
46.
Grünig E, Weissmann S, Ehlken N, Fijalkowska A, Fischer C, Fourme T, Galié N, Ghofrani A, Harrison RE, Huez S, Humbert M, Janssen B, Kober J, Koehler R, Machado RD, Mereles D, Naeije R, Olschewski H, Provencher S, Reichenberger F, Retailleau K, Rocchi G, Simonneau G, Torbicki A, Trembath R, Seeger W. Stress Doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia. Circulation. 2009;119:1747–1757. doi: 10.1161/CIRCULATIONAHA.108.800938.
47.
Kovacs G, Maier R, Aberer E, Brodmann M, Scheidl S, Tröster N, Hesse C, Salmhofer W, Graninger W, Gruenig E, Rubin LJ, Olschewski H. Borderline pulmonary arterial pressure is associated with decreased exercise capacity in scleroderma. Am J Respir Crit Care Med. 2009;180:881–886. doi: 10.1164/rccm.200904-0563OC.
48.
Lewis GD, Murphy RM, Shah RV, Pappagianopoulos PP, Malhotra R, Bloch KD, Systrom DM, Semigran MJ. Pulmonary vascular response patterns during exercise in left ventricular systolic dysfunction predict exercise capacity and outcomes. Circ Heart Fail. 2011;4:276–285. doi: 10.1161/CIRCHEARTFAILURE.110.959437.
49.
Naeije R, Vanderpool R, Dhakal BP, Saggar R, Saggar R, Vachiery JL, Lewis GD. Exercise-induced pulmonary hypertension: physiological basis and methodological concerns. Am J Respir Crit Care Med. 2013;187:576–583. doi: 10.1164/rccm.201211-2090CI.
50.
Naeije R. In defence of exercise stress tests for the diagnosis of pulmonary hypertension. Heart. 2011;97:94–95. doi: 10.1136/hrt.2010.212126.
51.
Saggar R, Lewis GD, Systrom DM, Champion HC, Naeije R, Saggar R. Pulmonary vascular responses to exercise: a haemodynamic observation. Eur Respir J. 2012;39:231–234. doi: 10.1183/09031936.00166211.
52.
D’Alto M, Ghio S, D’Andrea A, Pazzano AS, Argiento P, Camporotondo R, Allocca F, Scelsi L, Cuomo G, Caporali R, Cavagna L, Valentini G, Calabrò R. Inappropriate exercise-induced increase in pulmonary artery pressure in patients with systemic sclerosis. Heart. 2011;97:112–117. doi: 10.1136/hrt.2010.203471.
53.
Magne J, Lancellotti P, Piérard LA. Exercise pulmonary hypertension in asymptomatic degenerative mitral regurgitation. Circulation. 2010;122:33–41. doi: 10.1161/CIRCULATIONAHA.110.938241.
54.
La Gerche A, Burns AT, Mooney DJ, Inder WJ, Taylor AJ, Bogaert J, Macisaac AI, Heidbüchel H, Prior DL. Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes. Eur Heart J. 2012;33:998–1006. doi: 10.1093/eurheartj/ehr397.
55.
Reichek N. Right ventricular strain in pulmonary hypertension: flavor du jour or enduring prognostic index? Circ Cardiovasc Imaging. 2013;6:609–611. doi: 10.1161/CIRCIMAGING.113.000936.
56.
Gjesdal O, Edvardsen T. Tissue Doppler in ischemic heart disease., Fleming RM, ed. In: Establishing Better Standards of Care in Doppler Echocardiography, Computed Tomography and Nuclear Cardiology. Rijeka: InTech; 2011: 84–98. https://doi.org/10.5772/24458. Accessed February 10, 2015.
57.
Gjesdal O, Hopp E, Vartdal T, Lunde K, Helle-Valle T, Aakhus S, Smith HJ, Ihlen H, Edvardsen T. Global longitudinal strain measured by two-dimensional speckle tracking echocardiography is closely related to myocardial infarct size in chronic ischaemic heart disease. Clin Sci (Lond). 2007;113:287–296. doi: 10.1042/CS20070066.
58.
Bijnens BH, Cikes M, Claus P, Sutherland GR. Velocity and deformation imaging for the assessment of myocardial dysfunction. Eur J Echocardiogr. 2009;10:216–226. doi: 10.1093/ejechocard/jen323.
59.
Sutherland GR, Di Salvo G, Claus P, D’hooge J, Bijnens B. Strain and strain rate imaging: a new clinical approach to quantifying regional myocardial function. J Am Soc Echocardiogr. 2004;17:788–802. doi: 10.1016/j.echo.2004.03.027.
60.
Fine NM, Chen L, Bastiansen PM, Frantz RP, Pellikka PA, Oh JK, Kane GC. Outcome prediction by quantitative right ventricular function assessment in 575 subjects evaluated for pulmonary hypertension. Circ Cardiovasc Imaging. 2013;6:711–721. doi: 10.1161/CIRCIMAGING.113.000640.
61.
Ernande L, Cottin V, Leroux PY, Girerd N, Huez S, Mulliez A, Bergerot C, Ovize M, Mornex JF, Cordier JF, Naeije R, Derumeaux G. Right isovolumic contraction velocity predicts survival in pulmonary hypertension. J Am Soc Echocardiogr. 2013;26:297–306. doi: 10.1016/j.echo.2012.11.011.
62.
Kane GC, Maradit-Kremers H, Slusser JP, Scott CG, Frantz RP, McGoon MD. Integration of clinical and hemodynamic parameters in the prediction of long-term survival in patients with pulmonary arterial hypertension. Chest. 2011;139:1285–1293. doi: 10.1378/chest.10-1293.
63.
Yeo TC, Dujardin KS, Tei C, Mahoney DW, McGoon MD, Seward JB. Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol. 1998;81:1157–1161.
64.
Biswas S, Ananthasubramaniam K. Clinical utility of three-dimensional echocardiography for the evaluation of ventricular function. Cardiol Rev. 2013;21:184–195. doi: 10.1097/CRD.0b013e3182815af2.
65.
Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, Pennell DJ. Interstudy reproducibility of right ventricular volumes, function, and mass with cardiovascular magnetic resonance. Am Heart J. 2004;147:218–223. doi: 10.1016/j.ahj.2003.10.005.
66.
Katz J, Whang J, Boxt LM, Barst RJ. Estimation of right ventricular mass in normal subjects and in patients with primary pulmonary hypertension by nuclear magnetic resonance imaging. J Am Coll Cardiol. 1993;21:1475–1481.
67.
Pennell DJ, Sechtem UP, Higgins CB, Manning WJ, Pohost GM, Rademakers FE, van Rossum AC, Shaw LJ, Yucel EK; Society for Cardiovascular Magnetic Resonance; Working Group on Cardiovascular Magnetic Resonance of the European Society of Cardiology. Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report. Eur Heart J. 2004;25:1940–1965. doi: 10.1016/j.ehj.2004.06.040.
68.
Shors SM, Fung CW, François CJ, Finn JP, Fieno DS. Accurate quantification of right ventricular mass at MR imaging by using cine true fast imaging with steady-state precession: study in dogs. Radiology. 2004;230:383–388. doi: 10.1148/radiol.2302021309.
69.
van Wolferen SA, Marcus JT, Boonstra A, Marques KM, Bronzwaer JG, Spreeuwenberg MD, Postmus PE, Vonk-Noordegraaf A. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28:1250–1257. doi: 10.1093/eurheartj/ehl477.
70.
Jacobs W, van de Veerdonk MC, Trip P, de Man F, Heymans MW, Marcus JT, Kawut SM, Bogaard HJ, Boonstra A, Vonk Noordegraaf A. The right ventricle explains sex differences in survival in idiopathic pulmonary arterial hypertension. Chest. 2014;145:1230–1236. doi: 10.1378/chest.13-1291.
71.
Ventetuolo CE, Ouyang P, Bluemke DA, Tandri H, Barr RG, Bagiella E, Cappola AR, Bristow MR, Johnson C, Kronmal RA, Kizer JR, Lima JA, Kawut SM. Sex hormones are associated with right ventricular structure and function: the MESA-Right Ventricle Study. Am J Respir Crit Care Med. 2011;183:659–667. doi: 10.1164/rccm.201007-1027OC.
72.
Swift AJ, Rajaram S, Campbell MJ, Hurdman J, Thomas S, Capener D, Elliot C, Condliffe R, Wild JM, Kiely DG. Prognostic value of cardiovascular magnetic resonance imaging measurements corrected for age and sex in idiopathic pulmonary arterial hypertension. Circ Cardiovasc Imaging. 2014;7:100–106. doi: 10.1161/CIRCIMAGING.113.000338.
73.
Mauritz GJ, Vonk-Noordegraaf A, Kind T, Surie S, Kloek JJ, Bresser P, Saouti N, Bosboom J, Westerhof N, Marcus JT. Pulmonary endarterectomy normalizes interventricular dyssynchrony and right ventricular systolic wall stress. J Cardiovasc Magn Reson. 2012;14:5. doi: 10.1186/1532-429X-14-5.
74.
van de Veerdonk MC, Dusoswa SA, Tim Marcus J, Bogaard HJ, Spruijt O, Kind T, Westerhof N, Vonk-Noordegraaf A. The importance of trabecular hypertrophy in right ventricular adaptation to chronic pressure overload. Int J Cardiovasc Imag. 2013;30:357–365.
75.
Hagger D, Condliffe R, Woodhouse N, Elliot CA, Armstrong IJ, Davies C, Hill C, Akil M, Wild JM, Kiely DG. Ventricular mass index correlates with pulmonary artery pressure and predicts survival in suspected systemic sclerosis-associated pulmonary arterial hypertension. Rheumatology (Oxford). 2009;48:1137–1142. doi: 10.1093/rheumatology/kep187.
76.
Peacock AJ, Crawley S, McLure L, Blyth K, Vizza CD, Poscia R, Francone M, Iacucci I, Olschewski H, Kovacs G, Vonk Noordegraaf A, Marcus JT, van de Veerdonk MC, Oosterveer FP. Changes in right ventricular function measured by cardiac magnetic resonance imaging in patients receiving pulmonary arterial hypertension-targeted therapy: the EURO-MR study. Circ Cardiovasc Imaging. 2014;7:107–114. doi: 10.1161/CIRCIMAGING.113.000629.
77.
Saba TS, Foster J, Cockburn M, Cowan M, Peacock AJ. Ventricular mass index using magnetic resonance imaging accurately estimates pulmonary artery pressure. Eur Respir J. 2002;20:1519–1524.
78.
Hopkins WE, Ochoa LL, Richardson GW, Trulock EP. Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant. 1996;15(pt 1):100–105.
79.
Hopkins WE, Waggoner AD. Severe pulmonary hypertension without right ventricular failure: the unique hearts of patients with Eisenmenger syndrome. Am J Cardiol. 2002;89:34–38.
80.
Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest. 2009;135:794–804. doi: 10.1378/chest.08-0492.
81.
Kind T, Mauritz GJ, Marcus JT, van de Veerdonk M, Westerhof N, Vonk-Noordegraaf A. Right ventricular ejection fraction is better reflected by transverse rather than longitudinal wall motion in pulmonary hypertension. J Cardiovasc Magn Reson. 2010;12:35. doi: 10.1186/1532-429X-12-35.
82.
Mauritz GJ, Kind T, Marcus JT, Bogaard HJ, van de Veerdonk M, Postmus PE, Boonstra A, Westerhof N, Vonk-Noordegraaf A. Progressive changes in right ventricular geometric shortening and long-term survival in pulmonary arterial hypertension. Chest. 2012;141:935–943. doi: 10.1378/chest.10-3277.
83.
Petitjean C, Rougon N, Cluzel P. Assessment of myocardial function: a review of quantification methods and results using tagged MRI. J Cardiovasc Magn Reson. 2005;7:501–516.
84.
Fayad ZA, Ferrari VA, Kraitchman DL, Young AA, Palevsky HI, Bloomgarden DC, Axel L. Right ventricular regional function using MR tagging: normals versus chronic pulmonary hypertension. Magn Reson Med. 1998;39:116–123.
85.
Shehata ML, Harouni AA, Skrok J, Basha TA, Boyce D, Lechtzin N, Mathai SC, Girgis R, Osman NF, Lima JA, Bluemke DA, Hassoun PM, Vogel-Claussen J. Regional and global biventricular function in pulmonary arterial hypertension: a cardiac MR imaging study. Radiology. 2013;266:114–122. doi: 10.1148/radiol.12111599.
86.
Blyth KG, Groenning BA, Martin TN, Foster JE, Mark PB, Dargie HJ, Peacock AJ. Contrast enhanced-cardiovascular magnetic resonance imaging in patients with pulmonary hypertension. Eur Heart J. 2005;26:1993–1999. doi: 10.1093/eurheartj/ehi328.
87.
McCann GP, Beek AM, Vonk-Noordegraaf A, van Rossum AC. Delayed contrast-enhanced magnetic resonance imaging in pulmonary arterial hypertension. Circulation. 2005;112:e268. doi: 10.1161/CIRCULATIONAHA.104.512848.
88.
McCann GP, Gan CT, Beek AM, Niessen HW, Vonk Noordegraaf A, van Rossum AC. Extent of MRI delayed enhancement of myocardial mass is related to right ventricular dysfunction in pulmonary artery hypertension. AJR Am J Roentgenol. 2007;188:349–355. doi: 10.2214/AJR.05.1259.
89.
Sanz J, Dellegrottaglie S, Kariisa M, Sulica R, Poon M, O’Donnell TP, Mehta D, Fuster V, Rajagopalan S. Prevalence and correlates of septal delayed contrast enhancement in patients with pulmonary hypertension. Am J Cardiol. 2007;100:731–735. doi: 10.1016/j.amjcard.2007.03.094.
90.
Sanz J, García-Alvarez A, Fernández-Friera L, Nair A, Mirelis JG, Sawit ST, Pinney S, Fuster V. Right ventriculo-arterial coupling in pulmonary hypertension: a magnetic resonance study. Heart. 2012;98:238–243. doi: 10.1136/heartjnl-2011-300462.
91.
Kawel-Boehm N, Dellas Buser T, Greiser A, Bieri O, Bremerich J, Santini F. In-vivo assessment of normal T1 values of the right-ventricular myocardium by cardiac MRI. Int J Cardiovasc Imaging. 2014;30:323–328. doi: 10.1007/s10554-013-0326-3.
92.
Marcus JT, Gan CT, Zwanenburg JJ, Boonstra A, Allaart CP, Götte MJ, Vonk-Noordegraaf A. Interventricular mechanical asynchrony in pulmonary arterial hypertension: left-to-right delay in peak shortening is related to right ventricular overload and left ventricular underfilling. J Am Coll Cardiol. 2008;51:750–757. doi: 10.1016/j.jacc.2007.10.041.
93.
Marcus JT, Mauritz GJ, Kind T, Vonk-Noordegraaf A. Interventricular mechanical dyssynchrony in pulmonary arterial hypertension: early or delayed strain in the right ventricular free wall? Am J Cardiol. 2009;103:894–895. doi: 10.1016/j.amjcard.2009.01.002.
94.
Roeleveld RJ, Marcus JT, Boonstra A, Postmus PE, Marques KM, Bronzwaer JG, Vonk-Noordegraaf A. A comparison of noninvasive MRI-based methods of estimating pulmonary artery pressure in pulmonary hypertension. J Magn Reson Imaging. 2005;22:67–72. doi: 10.1002/jmri.20338.
95.
Gan C, Lankhaar JW, Marcus JT, Westerhof N, Marques KM, Bronzwaer JG, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Impaired left ventricular filling due to right-to-left ventricular interaction in patients with pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol. 2006;290:H1528–H1533. doi: 10.1152/ajpheart.01031.2005.
96.
Vogel-Claussen J, Skrok J, Shehata ML, Singh S, Sibley CT, Boyce DM, Lechtzin N, Girgis RE, Mathai SC, Goldstein TA, Zheng J, Lima JA, Bluemke DA, Hassoun PM. Right and left ventricular myocardial perfusion reserves correlate with right ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension. Radiology. 2011;258:119–127. doi: 10.1148/radiol.10100725.
97.
van Wolferen SA, Marcus JT, Westerhof N, Spreeuwenberg MD, Marques KM, Bronzwaer JG, Henkens IR, Gan CT, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Right coronary artery flow impairment in patients with pulmonary hypertension. Eur Heart J. 2008;29:120–127. doi: 10.1093/eurheartj/ehm567.
98.
Spindler M, Schmidt M, Geier O, Sandstede J, Hahn D, Ertl G, Beer M. Functional and metabolic recovery of the right ventricle during Bosentan therapy in idiopathic pulmonary arterial hypertension. J Cardiovasc Magn Reson. 2005;7:853–854.
99.
Hudsmith LE, Neubauer S. Magnetic resonance spectroscopy in myocardial disease. JACC Cardiovasc Imaging. 2009;2:87–96. doi: 10.1016/j.jcmg.2008.08.005.
100.
Dávila-Román VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, Gropler RJ. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2002;40:271–277.
101.
de las Fuentes L, Herrero P, Peterson LR, Kelly DP, Gropler RJ, Dávila-Román VG. Myocardial fatty acid metabolism: independent predictor of left ventricular mass in hypertensive heart disease. Hypertension. 2003;41:83–87.
102.
Nagaya N, Goto Y, Satoh T, Uematsu M, Hamada S, Kuribayashi S, Okano Y, Kyotani S, Shimotsu Y, Fukuchi K, Nakanishi N, Takamiya M, Ishida Y. Impaired regional fatty acid uptake and systolic dysfunction in hypertrophied right ventricle. J Nucl Med. 1998;39:1676–1680.
103.
Bergmann SR, Weinheimer CJ, Markham J, Herrero P. Quantitation of myocardial fatty acid metabolism using PET. J Nucl Med. 1996;37:1723–1730.
104.
Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J, Lopaschuk GD, Archer SL. The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med (Berl). 2010;88:47–60. doi: 10.1007/s00109-009-0524-6.
105.
Bokhari S, Raina A, Rosenweig EB, Schulze PC, Bokhari J, Einstein AJ, Barst RJ, Johnson LL. PET imaging may provide a novel biomarker and understanding of right ventricular dysfunction in patients with idiopathic pulmonary arterial hypertension. Circ Cardiovasc Imaging. 2011;4:641–647. doi: 10.1161/CIRCIMAGING.110.963207.
106.
Lundgrin EL, Park MM, Sharp J, Tang WH, Thomas JD, Asosingh K, Comhair SA, DiFilippo FP, Neumann DR, Davis L, Graham BB, Tuder RM, Dostanic I, Erzurum SC. Fasting 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 year. Ann Am Thorac Soc. 2013;10:1–9. doi: 10.1513/AnnalsATS.201206-029OC.
107.
Hagan G, Southwood M, Treacy C, Ross RM, Soon E, Coulson J, Sheares K, Screaton N, Pepke-Zaba J, Morrell NW, Rudd JH. (18)FDG PET imaging can quantify increased cellular metabolism in pulmonary arterial hypertension: a proof-of-principle study. Pulm Circ. 2011;1:448–455. doi: 10.4103/2045-8932.93543.
108.
Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J, Takahashi T, Nawata J, Ido T, Watanabe J, Shirato K. Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol. 2005;45:1849–1855. doi: 10.1016/j.jacc.2005.02.065.
109.
Kluge R, Barthel H, Pankau H, Seese A, Schauer J, Wirtz H, Seyfarth HJ, Steinbach J, Sabri O, Winkler J. Different mechanisms for changes in glucose uptake of the right and left ventricular myocardium in pulmonary hypertension. J Nucl Med. 2005;46:25–31.
110.
Can MM, Kaymaz C, Tanboga IH, Tokgoz HC, Canpolat N, Turkyilmaz E, Sonmez K, Ozdemir N. Increased right ventricular glucose metabolism in patients with pulmonary arterial hypertension. Clin Nucl Med. 2011;36:743–748. doi: 10.1097/RLU.0b013e3182177389.
111.
Fang W, Zhao L, Xiong CM, Ni XH, He ZX, He JG, Wilkins MR. Comparison of 18F-FDG uptake by right ventricular myocardium in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease. Pulm Circ. 2012;2:365–372. doi: 10.4103/2045-8932.101651.
112.
Wong YY, Ruiter G, Lubberink M, Raijmakers PG, Knaapen P, Marcus JT, Boonstra A, Lammertsma AA, Westerhof N, van der Laarse WJ, Vonk-Noordegraaf A. Right ventricular failure in idiopathic pulmonary arterial hypertension is associated with inefficient myocardial oxygen utilization. Circ Heart Fail. 2011;4:700–706. doi: 10.1161/CIRCHEARTFAILURE.111.962381.
113.
Sutendra G, Dromparis P, Paulin R, Zervopoulos S, Haromy A, Nagendran J, Michelakis ED. A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J Mol Med (Berl). 2013;91:1315–1327. doi: 10.1007/s00109-013-1059-4.
114.
Knaapen P, van Campen LM, de Cock CC, Götte MJ, Visser CA, Lammertsma AA, Visser FC. Effects of cardiac resynchronization therapy on myocardial perfusion reserve. Circulation. 2004;110:646–651. doi: 10.1161/01.CIR.0000138108687.19.C1.
115.
Wong YY, Raijmakers P, van Campen J, van der Laarse WJ, Knaapen P, Lubberink M, Ruiter G, Vonk Noordegraaf A, Lammertsma AA. 11C-acetate clearance as an index of oxygen consumption of the right myocardium in idiopathic pulmonary arterial hypertension: a validation study using 15O-labeled tracers and PET. J Nucl Med. 2013;54:1258–1262. doi: 10.2967/jnumed.112.115915.
116.
Wong YY, Westerhof N, Ruiter G, Lubberink M, Raijmakers P, Knaapen P, Marcus JT, Boonstra A, Lammertsma AA, van der Laarse WJ, Vonk-Noordegraaf A. Systolic pulmonary artery pressure and heart rate are main determinants of oxygen consumption in the right ventricular myocardium of patients with idiopathic pulmonary arterial hypertension. Eur J Heart Fail. 2011;13:1290–1295. doi: 10.1093/eurjhf/hfr140.
117.
Bogaard HJ, Natarajan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, Ockaili R, McCord JM, Voelkel NF. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation. 2009;120:1951–1960. doi: 10.1161/CIRCULATIONAHA.109.883843.
118.
de Man FS, Handoko ML, Guignabert C, Bogaard HJ, Vonk-Noordegraaf A. Neurohormonal axis in patients with pulmonary arterial hypertension: friend or foe? Am J Respir Crit Care Med. 2013;187:14–19. doi: 10.1164/rccm.201209-1663PP.
119.
Higuchi T, Bengel FM, Seidl S, Watzlowik P, Kessler H, Hegenloh R, Reder S, Nekolla SG, Wester HJ, Schwaiger M. Assessment of alphavbeta3 integrin expression after myocardial infarction by positron emission tomography. Cardiovasc Res. 2008;78:395–403. doi: 10.1093/cvr/cvn033.
120.
Meoli DF, Sadeghi MM, Krassilnikova S, Bourke BN, Giordano FJ, Dione DP, Su H, Edwards DS, Liu S, Harris TD, Madri JA, Zaret BL, Sinusas AJ. Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction. J Clin Invest. 2004;113:1684–1691. doi: 10.1172/JCI20352.
121.
Rodriguez-Porcel M, Cai W, Gheysens O, Willmann JK, Chen K, Wang H, Chen IY, He L, Wu JC, Li ZB, Mohamedali KA, Kim S, Rosenblum MG, Chen X, Gambhir SS. Imaging of VEGF receptor in a rat myocardial infarction model using PET. J Nucl Med. 2008;49:667–673. doi: 10.2967/jnumed.107.040576.
122.
Makowski MR, Ebersberger U, Nekolla S, Schwaiger M. In vivo molecular imaging of angiogenesis, targeting alphavbeta3 integrin expression, in a patient after acute myocardial infarction. Eur Heart J. 2008;29:2201. doi: 10.1093/eurheartj/ehn129.
123.
Caldwell JH, Link JM, Levy WC, Poole JE, Stratton JR. Evidence for pre- to postsynaptic mismatch of the cardiac sympathetic nervous system in ischemic congestive heart failure. J Nucl Med. 2008;49:234–241. doi: 10.2967/jnumed.107.044339.
124.
Pietilä M, Malminiemi K, Ukkonen H, Saraste M, Någren K, Lehikoinen P, Voipio-Pulkki LM. Reduced myocardial carbon-11 hydroxyephedrine retention is associated with poor prognosis in chronic heart failure. Eur J Nucl Med. 2001;28:373–376.
125.
Schäfers M, Dutka D, Rhodes CG, Lammertsma AA, Hermansen F, Schober O, Camici PG. Myocardial presynaptic and postsynaptic autonomic dysfunction in hypertrophic cardiomyopathy. Circ Res. 1998;82:57–62.
126.
de Man FS, Tu L, Handoko ML, Rain S, Ruiter G, François C, Schalij I, Dorfmüller P, Simonneau G, Fadel E, Perros F, Boonstra A, Postmus PE, van der Velden J, Vonk-Noordegraaf A, Humbert M, Eddahibi S, Guignabert C. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:780–789. doi: 10.1164/rccm.201203-0411OC.
127.
Fukushima K, Bravo PE, Higuchi T, Schuleri KH, Lin X, Abraham MR, Xia J, Mathews WB, Dannals RF, Lardo AC, Szabo Z, Bengel FM. Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin II type 1 receptors. J Am Coll Cardiol. 2012;60:2527–2534. doi: 10.1016/j.jacc.2012.09.023.
128.
Foo RS, Mani K, Kitsis RN. Death begets failure in the heart. J Clin Invest. 2005;115:565–571. doi: 10.1172/JCI24569.
129.
Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–219.
130.
Kietselaer BL, Reutelingsperger CP, Boersma HH, Heidendal GA, Liem IH, Crijns HJ, Narula J, Hofstra L. Noninvasive detection of programmed cell loss with 99mTc-labeled annexin A5 in heart failure. J Nucl Med. 2007;48:562–567.
131.
Narula J, Acio ER, Narula N, Samuels LE, Fyfe B, Wood D, Fitzpatrick JM, Raghunath PN, Tomaszewski JE, Kelly C, Steinmetz N, Green A, Tait JF, Leppo J, Blankenberg FG, Jain D, Strauss HW. Annexin-V imaging for noninvasive detection of cardiac allograft rejection. Nat Med. 2001;7:1347–1352. doi: 10.1038/nm1201-1347.
132.
Paffett ML, Hesterman J, Candelaria G, Lucas S, Anderson T, Irwin D, Hoppin J, Norenberg J, Campen MJ. Longitudinal in vivo SPECT/CT imaging reveals morphological changes and cardiopulmonary apoptosis in a rodent model of pulmonary arterial hypertension. PLoS One. 2012;7:e40910. doi: 10.1371/journal.pone.0040910.
133.
Nensa F, Poeppel TD, Beiderwellen K, Schelhorn J, Mahabadi AA, Erbel R, Heusch P, Nassenstein K, Bockisch A, Forsting M, Schlosser T. Hybrid PET/MR imaging of the heart: feasibility and initial results. Radiology. 2013;268:366–373. doi: 10.1148/radiol.13130231.
134.
Ibrahim T, Nekolla SG, Langwieser N, Rischpler C, Groha P, Laugwitz KL, Schwaiger M. Simultaneous positron emission tomography/magnetic resonance imaging identifies sustained regional abnormalities in cardiac metabolism and function in stress-induced transient midventricular ballooning syndrome: a variant of Takotsubo cardiomyopathy. Circulation. 2012;126:e324–e326. doi: 10.1161/CIRCULATIONAHA.112.134346.
135.
Schlosser T, Nensa F, Mahabadi AA, Poeppel TD. Hybrid MRI/PET of the heart: a new complementary imaging technique for simultaneous acquisition of MRI and PET data. Heart. 2013;99:351–352. doi: 10.1136/heartjnl-2012-302740.
136.
van Wolferen SA, Grünberg K, Vonk Noordegraaf A. Diagnosis and management of pulmonary hypertension over the past 100 years. Respir Med. 2007;101:389–398. doi: 10.1016/j.rmed.2006.11.022.
137.
Galiè N, Hinderliter AL, Torbicki A, Fourme T, Simonneau G, Pulido T, Espinola-Zavaleta N, Rocchi G, Manes A, Frantz R, Kurzyna M, Nagueh SF, Barst R, Channick R, Dujardin K, Kronenberg A, Leconte I, Rainisio M, Rubin L. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and Doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:1380–1386.
138.
Groepenhoff H, Vonk-Noordegraaf A, van de Veerdonk MC, Boonstra A, Westerhof N, Bogaard HJ. Prognostic relevance of changes in exercise test variables in pulmonary arterial hypertension. PLoS One. 2013;8:e72013. doi: 10.1371/journal.pone.0072013.
139.
Sosnovik DE, Schellenberger EA, Nahrendorf M, Novikov MS, Matsui T, Dai G, Reynolds F, Grazette L, Rosenzweig A, Weissleder R, Josephson L. Magnetic resonance imaging of cardiomyocyte apoptosis with a novel magneto-optical nanoparticle. Magn Reson Med. 2005;54:718–724. doi: 10.1002/mrm.20617.
140.
Zhao M, Beauregard DA, Loizou L, Davletov B, Brindle KM. Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent. Nat Med. 2001;7:1241–1244. doi: 10.1038/nm1101-1241.
141.
Keen HG, Dekker BA, Disley L, Hastings D, Lyons S, Reader AJ, Ottewell P, Watson A, Zweit J. Imaging apoptosis in vivo using 124I-annexin V and PET. Nucl Med Biol. 2005;32:395–402. doi: 10.1016/j.nucmedbio.2004.12.008.
142.
Conway MA, Allis J, Ouwerkerk R, Niioka T, Rajagopalan B, Radda GK. Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy. Lancet. 1991;338:973–976.
143.
Naya M, Tsukamoto T, Morita K, Katoh C, Nishijima K, Komatsu H, Yamada S, Kuge Y, Tamaki N, Tsutsui H. Myocardial beta-adrenergic receptor density assessed by 11C-CGP12177 PET predicts improvement of cardiac function after carvedilol treatment in patients with idiopathic dilated cardiomyopathy. J Nucl Med. 2009;50:220–225. doi: 10.2967/jnumed.108.056341.
144.
de Jong RM, Willemsen AT, Slart RH, Blanksma PK, van Waarde A, Cornel JH, Vaalburg W, van Veldhuisen DJ, Elsinga PH. Myocardial beta-adrenoceptor downregulation in idiopathic dilated cardiomyopathy measured in vivo with PET using the new radioligand (S)-[11C]CGP12388. Eur J Nucl Med Mol Imaging. 2005;32:443–447. doi: 10.1007/s00259-004-1701-z.
145.
Le Guludec D, Cohen-Solal A, Delforge J, Delahaye N, Syrota A, Merlet P. Increased myocardial muscarinic receptor density in idiopathic dilated cardiomyopathy: an in vivo PET study. Circulation. 1997;96:3416–3422.
Information & Authors
Information
Published In
Copyright
© 2015 American Heart Association, Inc.
History
Published online: 10 March 2015
Published in print: 10 March 2015
Keywords
Subjects
Authors
Disclosures
None.
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
- Assessment of right ventricular systolic function using speckle tracking strain imaging in patients with severe tricuspid regurgitation: a validation study with cardiac magnetic resonance, Journal of Cardiovascular Imaging, 32, 1, (2024).https://doi.org/10.1186/s44348-024-00015-4
- Defining Echocardiographic Degrees of Right Heart Size and Function in Pulmonary Vascular Disease From the PVDOMICS Study, Circulation: Cardiovascular Imaging, 17, 10, (e017074), (2024)./doi/10.1161/CIRCIMAGING.124.017074
- Comparison of admittance and cardiac magnetic resonance generated pressure-volume loops in a porcine model, Physiological Measurement, 45, 5, (055014), (2024).https://doi.org/10.1088/1361-6579/ad4a03
- State-of-the Art Cardiac Magnetic Resonance in Pulmonary Hypertension – An Update on Diagnosis, Risk Stratification and Treatment, Trends in Cardiovascular Medicine, 34, 3, (161-171), (2024).https://doi.org/10.1016/j.tcm.2022.12.005
- Prognostic Value of Echocardiographic Coupling Metrics in Systemic Sclerosis–Associated Pulmonary Vascular Disease, Journal of the American Society of Echocardiography, (2024).https://doi.org/10.1016/j.echo.2024.09.010
- Time-Resolved 3D cardiopulmonary MRI reconstruction using spatial transformer network, Mathematical Biosciences and Engineering, 20, 9, (15982-15998), (2023).https://doi.org/10.3934/mbe.2023712
- Clinical Usefulness of Right Ventricle–Pulmonary Artery Coupling in Cardiovascular Disease, Journal of Clinical Medicine, 12, 7, (2526), (2023).https://doi.org/10.3390/jcm12072526
- The Heroic Chamber – an Outlook on the Right Ventricle in Eisenmenger Syndrome, Romanian Journal of Cardiology, 31, 4, (837-846), (2022).https://doi.org/10.47803/rjc.2020.31.4.837
- Normal Echocardiographic Reference Values of the Right Ventricular to Left Ventricular Endsystolic Diameter Ratio and the Left Ventricular Endsystolic Eccentricity Index in Healthy Children and in Children With Pulmonary Hypertension, Frontiers in Cardiovascular Medicine, 9, (2022).https://doi.org/10.3389/fcvm.2022.950765
- Pathobiology of Right Ventricular Failure, Encyclopedia of Respiratory Medicine, (542-551), (2022).https://doi.org/10.1016/B978-0-12-801238-3.11563-6
- See more
Loading...
View Options
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
Purchase this article to access the full text.
eLetters(0)
eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.
Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.